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Sunday, September 1, 2024

Papaver somniferum

From Wikipedia, the free encyclopedia
Papaver somniferum
Scientific classification Edit this classification
Kingdom: Plantae
Clade: Tracheophytes
Clade: Angiosperms
Clade: Eudicots
Order: Ranunculales
Family: Papaveraceae
Genus: Papaver
Species:
P. somniferum
Binomial name
Papaver somniferum

Papaver somniferum, commonly known as the opium poppy or breadseed poppy, is a species of flowering plant in the family Papaveraceae. It is the species of plant from which both opium and poppy seeds are derived and is also a valuable ornamental plant grown in gardens. Its native range was east of the Mediterranean Sea, but has since been obscured and vastly expanded by introduction and cultivation from ancient times to the present day, being naturalized across much of Europe and Asia.

This poppy is grown as an agricultural crop on a large scale, for one of three primary purposes: to produce poppy seeds, to produce opium (for use mainly by the pharmaceutical industry), and to produce other alkaloids (mainly thebaine and oripavine) that are processed by pharmaceutical companies into drugs such as hydrocodone and oxycodone. Each of these goals has special breeds that are targeted at one of these businesses, and breeding efforts (including biotechnological ones) are continually underway. A comparatively small amount of P. somniferum is also produced commercially for ornamental purposes.

Today many varieties have been bred that do not produce a significant quantity of opium. The cultivar 'Sujata' produces no latex at all. Breadseed poppy is more accurate as a common name today because all varieties of P. somniferum produce edible seeds. This differentiation has strong implications for legal policy surrounding the growing of this plant.

Description

Papaver somniferum is an annual herb growing to about 100 centimetres (40 inches) tall. The plant is strongly glaucous, giving a greyish-green appearance, and the stem and leaves bear a sparse distribution of coarse hairs. The large leaves are lobed, the upper stem leaves clasping the stem, the lowest leaves with a short petiole. The flowers are up to 3–10 cm (1–4 in) diameter, normally with four white, mauve or red petals, sometimes with dark markings at the base. The fruit is a hairless, rounded capsule topped with 12–18 radiating stigmatic rays, or fluted cap. All parts of the plant exude white latex when wounded.

Metabolism

The alkaloids are organic nitrogenous compounds, derivatives of secondary metabolism, synthesized through the metabolic pathway of benzylisoquinoline. First, the amino acid phenylalanine, through the enzyme phenylalanine hydroxylase, is transformed into tyrosine. Tyrosine can follow two different routes: by tyrosine hydroxylase it can form L-dopamine (L-DOPA), or it can be reduced to form 4-phenylhydroxyacetaldehyde (4-HPAA). Subsequently, L-DOPA reacts with 4-HPAA and, through a series of reactions, forms (S) -norcoclaurine, which carries the benzylisoquinoline skeleton that gives its name to this pathway. The conversion of (S) -norcoclaurin to (S) -reticuline is one of the key points, since from (S) -reticuline morphine can be formed through the morphinan route, noscapine through the path of the noscapina or berberina.

Genome

The poppy genome contains 51,213 genes encoding proteins distributed 81.6% in 11 individual chromosomes and 18.4% remaining in unplaced scaffolds. In addition, 70.9% of the genome is made up of repetitive elements, of which the most represented are the long terminal repeat retrotransposons. This enrichment of genes is related to the maintenance of homeostasis and a positive regulation of transcription.

The analysis of synergy of the opium poppy reveals traces of segmental duplications 110 million years ago (MYA), before the divergence between Papaveraceae and Ranunculaceae, and an event of duplication of the complete genome makes 7.8 MYA.

The genes are possibly grouped as follows:

  • The genes responsible for the conversion of (S) -reticuline to noscapine are found on chromosome 11.
  • The genes responsible for the conversion of (S) -reticuline to thebaine are found on chromosome 11.
  • The genes responsible for the conversion of thebaine are found in chromosome 1, chromosome 2, chromosome 7, and perhaps others.

Taxonomy

Papaver somniferum was formally described by the Swedish botanist Carl Linnaeus in his seminal publication Species Plantarum in 1753 on page 508.

Varieties and cultivars

P. somniferum has had a very long tradition of use, starting in the Neolithic. This long period of time allowed the development of a broad range of different forms. In total there are 52 botanical varieties. Breeding of P. somniferum faces a challenge caused by the contradictory breeding goals for this species. On one hand a very high content of alkaloids is requested for medical uses. The global demand for the alkaloids and the pharmaceutical derivatives has increased in the past years. Therefore, there is a need for the development of varieties with a high opium yield. On the other hand, the food industry demands as low alkaloid contents as possible.

There is one accepted subspecies, P. somniferum subsp. setigerum (DC.) Arcang. There are also many varieties and cultivars. Colors of the flowers vary widely, as do other physical characteristics, such as number and shape of petals, number of flowers and fruits, number of seeds, color of seeds, and production of opium. Papaver somniferum var. paeoniflorum is a variety with flowers that are highly double, and are grown in many colors. P. somniferum var. laciniatum is a variety with flowers that are highly double and deeply lobed. The variety Sujata produces no latex and no commercial utility for opioid production.

Distribution and habitat

The native range of opium poppy is probably the Eastern Mediterranean, but extensive cultivation and introduction of the species throughout Europe since ancient times have obscured its origin. It has escaped from cultivation, or has been introduced and become naturalized extensively in all regions of the British Isles, particularly in the south and east and in almost all other countries of the world with suitable, temperate climates.

Ecology

Diseases

P. somniferum is susceptible to several fungal, insect and virus infections including seed borne diseases such as downy mildew and root rot. The use of pesticides in combination to cultural methods have been considered as major control measures for various poppy diseases.

The fungal pathogen Peronospora arborescens, the causal agent of downy mildew, occurs preferentially during wet and humid conditions. This oomycete penetrates the roots through oospores and infects the leaves as conidia in a secondary infection. The fungus causes hypertrophy and curvature of the stem and flower stalks. The symptoms are chlorosis and curling of the affected tissues with necrotic spots. The leaf under-surface is covered with a downy mildew coating containing conidiospores that spread the infection further leading to plant damage and death. Another downy mildew species, Peronospora somniferi, produces systemic infections leading to stunting and deformation of poppy plants. Downy mildew can be controlled preventively at the initial stage of seed development through several fungicide applications.

Leaf blight caused by the fungus Helminthosporium papaveris is one of the most destructive poppy diseases worldwide. The seed-borne fungus causes root rot in young plants and stunted stems in plants at a higher development stage, where leaf spots appear on the leaves and is being transmitted to capsules and seeds. Early sowing of seeds and deep plowing of poppy residues can reduce fungal inoculum during the plant growing season in the following year on neighboring poppy stocks, respectively.

Mosaic diseases in p. somniferum are caused by rattle virus and the Carlavirus. In 2006, a novel virus tentatively called "opium poppy mosaic virus" (OPMV) from the genus Umbravirus was isolated from p. somniferum containing leaf mosaic and mottling symptoms, in New Zealand.

Pests

There are only a few pests that can do harm to P. somniferum.

Flea beetles perforate the leaves of young plants and aphids suck on the sap of the flower buds. The poppy root weevil (Stenocarus ruficornis) is another significant pest. The insect lives in the soil and migrates in spring to the poppy fields after crop emergence. Adults damage the leaves of small plants by eating them. Female lay their eggs into the tissue of lower leaves. Insect larvae hatch and burrow into the soil to complete their life cycle on the poppy roots as adults.

Cultivation

In the growth development of P. somniferum, six stages can be distinguished. The growth development starts with the growth of the seedlings. In a second step the rosette-type leaves and stalks are formed. After that budding (hook stage) takes place as a third step. The hook stage is followed by flowering. Subsequently, technical maturity is reached, which means that the plant is ready for cutting. The last step is biological maturity; dry seeds are ripened. The photoperiod seems to be the main determinant of flower development of P. somniferum.

P. somniferum shows a very slow development in the beginning of its vegetation period. Due to this fact the competition of weeds is very high in early stages. It is very important to control weeds effectively in the first 50 days after sowing. Additionally, Papaver somniferum is rather susceptible to herbicides. The pre-emergence application of the herbicide chlortoluron has been shown to be effective in reducing weed levels. However, in the last decade the weed management of Papaver somniferum has shifted from pre-emergence treatments to post-emergence treatments. Especially, the application of the two herbicides mesotrione and tembotrione has become very popular. The combined application of those two herbicides has been shown to be recommendable for effective weed management in Papaver somniferum. Sowing time (autumn or spring), preceding crop and soil texture are important variables influencing the weed species composition. A highly abundant weed species in Papaver somniferum fields was shown to be Papaver rhoeas. Papaver somniferum and Papaver rhoeas are congeners and belong to the same plant family, which impedes the chemical control of this weed species. Therefore, weed management represents a big challenge and requires technological knowledge from the farmer. In order to increase the efficiency of weed control not only chemical weed control should be applied but also mechanical weed control.

For P. somniferum, a growth density of 70 to 80 plants per square meter is recommended. Latex-to-biomass yield is greatest under conditions of slight water deficit.

Ornamental

Live plants and seeds of the opium poppy are widely sold by seed companies and nurseries in most of the western world, including the United States. Poppies are sought after by gardeners for the vivid coloration of the blooms, the hardiness and reliability of the poppy plants, the exotic chocolate-vegetal fragrance note of some cultivars, and the ease of growing the plants from purchased flats of seedlings or by direct sowing of the seed. Poppy seed pods are also sold for dried flower arrangements.

Though "opium poppy and poppy straw" are listed in Schedule II of the United States' Controlled Substances Act, P. somniferum can be grown legally in the United States as a seed crop or ornamental flower. During the summer, opium poppies can be seen flowering in gardens throughout North America and Europe, and displays are found in many private plantings, as well as in public botanical and museum gardens such as United States Botanical Garden, Missouri Botanical Garden, and North Carolina Botanical Garden.

Many countries grow the plants, and some rely heavily on the commercial production of the drug as a major source of income. As an additional source of profit, the seeds of the same plants are sold for use in foods, so the cultivation of the plant is a significant source of income. This international trade in seeds of P. somniferum was addressed by a UN resolution "to fight the international trade in illicit opium poppy seeds" on 28 July 1998.

Production

Poppy seed production – 2018
Country (tonnes)
 Turkey 26,991
 Czech Republic 13,666
 Spain 12,360
World 76,240
Source: FAOSTAT of the United Nations

Food

In 2018, world production of poppy seeds for consumption was 76,240 tonnes, led by Turkey with 35% of the world total (table). Poppy seed production and trade are susceptible to fluctuations mainly due to unstable yields. The performance of most genotypes of Papaver somniferum is very susceptible to environmental changes. This behaviour led to a stagnation of the poppy seed market value between 2008–2009 as a consequence of high stock levels, bad weather and poor quality. The world leading importer of poppy seed is India (16 000 tonnes), followed by Russia, Poland and Germany.

Poppy seed oil remains a niche product due to the lower yield compared to conventional oil crops.

Medicine

Australia (Tasmania), Turkey and India are the major producers of poppy for medicinal purposes and poppy-based drugs, such as morphine or codeine. The New York Times reported, in 2014, that Tasmania was the largest producer of the poppy cultivars used for thebaine (85% of the world's supply) and oripavine (100% of the world's supply) production. Tasmania also had 25% of the world's opium and codeine production.

Restrictions

Opium poppy fields near Metheringham, Lincolnshire, England. Also visible in the field are red field poppies, another related species of poppy which often grows alongside P. somniferum as a weed

In most of Central Europe, poppy seed is commonly used for traditional pastries and cakes, and it is legal to grow poppies throughout the region, although Germany requires a licence.

Since January 1999 in the Czech Republic, according to the 167/1998 Sb. Addictive Substances Act, poppies growing in fields larger than 100 square metres (120 sq yd) is obliged for reporting to the local Custom Office. Extraction of opium from the plants is prohibited by law (§ 15 letter d/ of the act). It is also prohibited to grow varieties with more than 0.8% of morphine in dry matter of their capsules, excluding research and experimental purposes (§24/1b/ of the act). The name Czech blue poppy refers to blue poppy seeds used for food.

The United Kingdom does not require a licence for opium poppy cultivation, but does for extracting opium for medicinal products.

In the United States, opium poppies and poppy straw are prohibited. As the opium poppy is legal for culinary or esthetic reasons, poppies were once grown as a cash crop by farmers in California. The law of poppy cultivation in the United States is somewhat ambiguous. The reason for the ambiguity is that the Opium Poppy Control Act of 1942 (now repealed) stated that any opium poppies should be declared illegal, even if the farmers were issued a state permit. § 3 of the Opium Poppy Control Act stated:

It shall be unlawful for any person who is not the holder of a license authorizing him to produce the opium poppy, duly issued to him by the Secretary of the Treasury in accordance with the provisions of this Act, to produce the opium poppy, or to permit the production of the opium poppy in or upon any place owned, occupied, used, or controlled by him.

This led to the Poppy Rebellion, and to the Narcotics Bureau arresting anyone planting opium poppies and forcing the destruction of poppy fields of anyone who defied the prohibition of poppy cultivation. Though the press of those days favored the Federal Bureau of Narcotics, the state of California supported the farmers who grew opium poppies for their seeds for uses in foods such as poppy seed muffins. Today, this area of law has remained vague and remains somewhat controversial in the United States. The Opium Poppy Control Act of 1942 was repealed on 27 October 1970.

Under the Federal Controlled Substances Act, opium poppy and poppy straw are listed as Schedule II drugs under ACSN 9630. Most (all?) states also use this classification under the uniform penal code. Possession of a Schedule II drug is a federal and state felony.

Canada forbids possessing, seeking or obtaining the opium poppy (Papaver somniferum), its preparations, derivatives, alkaloids and salts, although an exception is made for poppy seed.

In some parts of Australia, P. somniferum is illegal to cultivate, but in Tasmania, some 50% of the world supply is cultivated.

In New Zealand, it is legal to cultivate the opium poppy as long as it is not used to produce controlled drugs.

In United Arab Emirates the cultivation of the opium poppy is illegal, as is possession of poppy seed. At least one man has been imprisoned for possessing poppy seed obtained from a bread roll.

Burma bans cultivation in certain provinces. In northern Burma bans have ended a century-old tradition of growing the opium poppy. Between 20,000 and 30,000 former poppy farmers left the Kokang region as a result of the ban in 2002. People from the Wa region, where the ban was implemented in 2005, fled to areas where growing opium is still possible.

In South Korea, the cultivation of the opium poppy is strictly prohibited.

Uses

History

Use of the opium poppy predates written history. The making and use of opium was known to the ancient Minoans. Its sap was later named opion by the ancient Greeks. The English name is based on the Latin adaptation of the Greek form. Evidence of the early domestication of opium poppy has been discovered through small botanical remains found in regions of the Mediterranean and west of the Rhine River, predating circa 5000 BC. These samples found in various Neolithic sites show the incredibly early cultivation and natural spread of the plant throughout western Europe.

Opium was used for treating asthma, stomach illnesses, and bad eyesight.

Opium became a major colonial commodity, moving legally and illegally through trade networks on the Indian subcontinent, Colonial America, Qing China and others. Members of the East India Company saw the opium trade as an investment opportunity beginning in 1683. In 1773, the Governor of Bengal established a monopoly on the production of Bengal opium, on behalf of the East India Company administration. The cultivation and manufacture of Indian opium was further centralized and controlled through a series of acts issued between 1797 and 1949.[62][63] East India Company merchants balanced an economic deficit from the importation of Chinese tea by selling Indian opium which was smuggled into China in defiance of Qing government bans. This trade led to the First and Second Opium Wars.

Many modern writers, particularly in the 19th century, have written on the opium poppy and its effects, notably Thomas de Quincey in Confessions of an English Opium Eater.

The French Romantic composer Hector Berlioz used opium for inspiration, subsequently producing his Symphonie Fantastique. In this work, a young artist overdoses on opium and experiences a series of visions of his unrequited love.

In the US, the Drug Enforcement Administration raided Thomas Jefferson's Monticello estate in 1987. It removed the poppy plants that had been planted continually there since Jefferson was alive and using opium from them. Employees of the foundation also destroyed gift shop items like shirts depicting the poppy and packets of the heirloom seed.

Poppy seeds and oil

Dried blue, grey and white poppy seeds used for pastries in Germany
Polish makowiec, a nut roll filled with poppy seed paste

Poppy seeds from Papaver somniferum are an important food item and the source of poppy seed oil, an edible oil that has many uses. The seeds contain very low levels of opiates and the oil extracted from them contains even less. Both the oil and the seed residue also have commercial uses.

The poppy press cake as a residue of the oil pressing can be used as fodder for different animals as e.g., poultry and fancy fowls. Especially in the time of the molt of the birds, the cake is nutritive and fits to their special needs. Next to the animal fodder, poppy offers other by-products. For example, the stem of the plant can be used for energy briquettes and pellets to heat.

Poppy seeds are used as a food in many cultures. They may be used whole by bakers to decorate their products or milled and mixed with sugar as a sweet filling. They have a creamy and nut-like flavor, and when used with ground coconut, the seeds provide a unique and flavour-rich curry base. They can be dry roasted and ground to be used in wet curry (curry paste) or dry curry.

When the European Union attempted to ban the cultivation of Papaver somniferum by private individuals on a small scale (such as personal gardens), citizens in EU countries where poppy seed is eaten heavily, such as countries in the Central-Eastern region, strongly resisted the plan, causing the EU to change course. Singapore, UAE, and Saudi Arabia are among nations that ban even having poppy seeds, not just growing the plants for them. The UAE has a long prison sentence for anyone possessing poppy seeds.

Opiates

Dried poppy seed pods and stems (plate), and seeds (bowl)

The opium poppy, as its name indicates, is the principal source of opium, the dried latex produced by the seed pods. Opium contains a class of naturally occurring alkaloids known as opiates, that include morphine, codeine, thebaine, oripavine, papaverine and noscapine. The specific epithet somniferum means "sleep-bringing", referring to the sedative properties of some of these opiates.

The opiate drugs are extracted from opium. The latex oozes from incisions made on the green seed pods and is collected once dry. Tincture of opium or laudanum, consisting of opium dissolved in alcohol or a mixture of alcohol and water, is one of many unapproved drugs regulated by the U.S. Food and Drug Administration (FDA). Its marketing and distribution persists because its historical use preceded the Federal Food, Drug & Cosmetic Act of 1938. Tincture of opium B.P., containing 1% w/v of anhydrous morphine, also remains in the British Pharmacopoeia, listed as a Class A substance under the Misuse of Drugs Act 1971.

Morphine is the predominant alkaloid found in the cultivated varieties of opium poppy that are used for opium production. Other varieties produce minimal opium or none at all, such as the latex-free Sujata type. Non-opium cultivars that are planted for drug production feature a high level of thebaine or oripavine. Those are refined into drugs like oxycodone. Raw opium contains about 8–14% morphine by dry weight, or more in high-yield cultivars. It may be used directly or chemically modified to produce semi-synthetic opioids such as heroin.

Culture

Opium poppies (flower and fruit) appear on the coat of arms of the Royal College of Anaesthetists.

Grayanotoxin

From Wikipedia, the free encyclopedia
https://en.wikipedia.org/wiki/Grayanotoxin

Grayanotoxins are a group of closely related neurotoxins named after Leucothoe grayana, a plant native to Japan and named for 19th-century American botanist Asa Gray. Grayanotoxin I (grayanotoxane-3,5,6,10,14,16-hexol 14-acetate) is also known as andromedotoxin, acetylandromedol, rhodotoxin and asebotoxin. Grayanotoxins are produced by Rhododendron species and other plants in the family Ericaceae. Honey made from the nectar and so containing pollen of these plants also contains grayanotoxins and is commonly referred to as mad honey.

Consumption of the plant or any of its secondary products, including mad honey, can cause a rare poisonous reaction called grayanotoxin poisoning, mad honey disease, honey intoxication, or rhododendron poisoning. It is most frequently produced and consumed in regions of Turkey and Nepal as a recreational drug and traditional medicine.

Origin

Rhododendron luteum

Grayanotoxins are produced by plants in the family Ericaceae, specifically members of the genera Agarista, Craibiodendron, Kalmia, Leucothoe, Lyonia, Pieris and Rhododendron. The genus Rhododendron alone encompasses over 750 species that grow around the world in parts of Europe, North America, Japan, Nepal and Turkey. They can grow at a variety of altitudes, ranging from sea level to more than 3 kilometres (9,800 ft). While many of these species contain grayanotoxins, only a few contain significant levels. Species with high concentrations of grayanotoxins, such as R. ponticum and R. luteum, are most commonly found in regions of Turkey bordering the Black Sea, and in Nepal.

Rhododendron ponticum

Nearly all parts of grayanotoxin-producing rhododendrons contain the molecule, including the stem, leaves, flower, pollen and nectar. Grayanotoxins can also be found in secondary plant products, such as honey, labrador tea, cigarettes, and herbal medicines.

Chemical structure

Grayanotoxin R1 R2 R3
Grayanotoxin I OH CH3 Ac
Grayanotoxin II CH2 H
Grayanotoxin III OH CH3 H
Grayanotoxin IV CH2 Ac

Grayanotoxins are low molecular weight hydrophobic compounds. They are structurally characterized as polyhydroxylated cyclic diterpenes. The base structure is a 5/7/6/5 ring system that does not contain nitrogen. More than 25 grayanotoxin isoforms have been identified from Rhododendron species, but grayanotoxin I and III are thought to be the principal toxic isoforms. Different Rhododendron species contain multiple different grayanotoxin isoforms, contributing to differences in plant toxicity.

Mechanism of action

Voltage-gated sodium channel with group II receptor site domains highlighted in red.

The toxicity of grayanotoxin is derived from its ability to interfere with voltage-gated sodium channels located in the cell membrane of neurons. The Nav1.x channels consist of four homologous domains (I-IV), each containing six transmembrane alpha-helical segments (S1-S6). Grayanotoxin has a binding affinity (IC50) of approximately 10 μM and binds the group II receptor site located on segment 6 of domains I and IV (IS6 and IVS6). Other toxins that bind to this region include the alkaloids veratridine, batrachotoxin and aconitine.

Experiments using squid axonal membranes indicate that sodium channel binding likely occurs on the internal face of the neuron. Additionally, grayanotoxin only binds to the activated conformation of sodium channels. Normally, voltage gated sodium channels are activated (opened) only when the cell membrane potential reaches a specific threshold voltage. This activated conformation allows for an influx of sodium ions resulting in cell depolarization, followed by the firing of an action potential. At the peak of the action potential, voltage-gated sodium channels are quickly inactivated and are only reset once the cell has repolarized to resting potential. When grayanotoxin is present, binding induces further conformational changes that prevent sodium channel inactivation and lead to a prolonged depolarization. Owing to its transient ability to activate channels and increase membrane permeability to sodium ions, grayanotoxin is classified as a reversible Nav1.x agonist.

Clinical effects

Although mad honey is used in traditional medicine in Turkey, the majority of grayanotoxin poisoning cases occur in middle-aged males who use the honey for perceived sexual enhancement. Slowing of heart rate and lowering of blood pressure are typical effects reported in one review of cases. Dizziness, nausea, fainting, and weakness were reported as common neurological outcomes. Other early-onset symptoms may include doubled and blurred vision, hypersalivation, perspiration, and paresthesia in the extremities and around the mouth. In higher doses, symptoms can include loss of coordination, severe and progressive muscular weakness, electrocardiographic changes of bundle branch block or ST-segment elevations as seen in ischemic myocardial threat, and nodal rhythm or Wolff-Parkinson-White syndrome.

The primary mediator of this grayanotoxin pathophysiology is the paired vagus nerve (tenth cranial nerve). The vagus nerve is a major component of the parasympathetic nervous system (a branch of the autonomic nervous system) and innervates various organs including the lungs, stomach, kidney and heart. Vagal stimulation of the heart is mediated by M2-subtype muscarinic acetylcholine receptors (mAChR). In severe cases of grayanotoxin poisoning, atropine – a non-specific "mAChR antagonist" or Muscarinic antagonist – can be used to treat bradycardia and other heart rhythm malfunctions. In addition to correcting rhythm disorders, administration of fluids and vasopressors can also help treat hypotension and mitigate other symptoms.

Patients exposed to low doses of grayanotoxin typically recover within a few hours. In more severe cases, symptoms may persist for 24 hours or longer and may require medical treatment (as described above). Despite the risk from cardiac problems, grayanotoxin poisoning is rarely fatal in humans.

Animal poisoning

In contrast to humans, grayanotoxin poisoning can be lethal for other animals. Nectar containing grayanotoxin can kill honeybees, though some seem to have resistance to it and can produce honey from the nectar (see below). According to a team of researchers from the UK and Ireland, worker bumblebees are not harmed and may be preferable as pollinators because they transfer more pollen. Consequently, it may be advantageous for plants to produce grayanotoxin to be pollinated by bumblebees.

Mad honey intoxication

Bees that collect pollen and nectar from grayanotoxin-containing plants often produce honey that also contains grayanotoxins. This so-called "mad honey" is the most common cause of grayanotoxin poisoning in humans. Small-scale producers of mad honey typically harvest honey from a small area or single hive to produce a final product containing a significant concentration of grayanotoxin. In contrast, large-scale honey production often mixes honey gathered from different locations, diluting the concentration of any contaminated honey.

Mad honey is produced in specific world regions, notably the Black Sea region of Turkey (91% of poisoning cases in one analysis) and Nepal (5%). In Turkey, mad honey known as deli bal is used as a recreational drug and traditional medicine. It is most commonly made from the nectar of Rhododendron luteum and Rhododendron ponticum in the Caucasus region. In Nepal, this type of honey is used by the Gurung people for both its hallucinogenic properties and supposed medicinal benefits.

In the 18th century, this honey was exported to Europe to add to alcoholic drinks to give them extra potency. In modern times, it is consumed locally and exported to North America, Europe and Asia.

Other grayanotoxin sources

In addition to various Rhododendron species, mad honey can also be made from several other grayanotoxin-containing plants. Honey produced from the nectar of Andromeda polifolia contains high enough levels of grayanotoxin to cause full body paralysis and potentially fatal breathing difficulties due to diaphragm paralysis. Honey obtained from spoonwood and allied species such as sheep-laurel can also cause illness. The honey from Lestrimelitta limao also produces a similar paralyzing effect to that of the honey from A. polifolia and is also toxic to humans.

Historical use

The intoxicating effects of mad honey have been suspected for centuries, including records from Xenophon, Aristotle, Strabo, Pliny the Elder and Columella, all reporting illness from eating "maddening" honey believed to be from the pollen or nectar of Rhododendron luteum and Rhododendron ponticum. According to Xenophon's Anabasis, an invading Greek army was accidentally poisoned by harvesting and eating the local Asia Minor honey, but they all made a quick recovery without any fatalities. Having heard of this incident, and realizing that foreign invaders would be ignorant of the dangers of the local honey, King Mithridates later used the honey as a deliberate poison when Pompey's army attacked the Heptakometes in Asia Minor in 69 BC. The Roman soldiers became delirious and nauseated after being tricked into eating the toxic honey, at which point Mithridates' army attacked.

Pollinator decline

From Wikipedia, the free encyclopedia
https://en.wikipedia.org/wiki/Pollinator_decline
A dead carpenter bee

Pollinator decline is the reduction in abundance of insect and other animal pollinators in many ecosystems worldwide that began being recorded at the end of the 20th century. Multiple lines of evidence exist for the reduction of wild pollinator populations at the regional level, especially within Europe and North America. Similar findings from studies in South America, China and Japan make it reasonable to suggest that declines are occurring around the globe. The majority of studies focus on bees, particularly honeybee and bumblebee species, with a smaller number involving hoverflies and lepidopterans.

The picture for domesticated pollinator species is less clear. Although the number of managed honey bee colonies in Europe and North America declined by 25% and 59% between 1985-2005 and 1947-2005 respectively, overall global stocks increased due to major hive number increases in countries such as China and Argentina. Nevertheless, in the time managed honeybee hives increased by 45% demand for animal pollinated crops tripled, highlighting the danger of relying on domesticated populations for pollination services.

Pollinators participate in the sexual reproduction of many plants by ensuring cross-pollination, essential for some species and a major factor in ensuring genetic diversity for others. Since plants are the primary food source for animals, the possible reduction or disappearance of pollinators has been referred to as an "armageddon" by some journalists.

Evidence

The declines in abundance and diversity of insect pollinators over the twentieth century have been documented in highly industrialized regions of the world, particularly northwestern Europe and eastern North America.

Colony collapse disorder has attracted much public attention. According to a 2013 blog the winter losses of beehives had increased in recent years in Europe and the United States, with a hive failure rate up to 50%.

A 2017 German study, using 1,500 samples from 63 sites, indicated that the biomass of flying insects in that area had declined by three-quarters in the previous 25 years. One 2009 study stated that while the bee population had increased by 45% over the past 50 years, the amount of crops which use bees had increased by 300%; although there is absolutely no evidence this has caused any problems, the authors propose it might cause "future pollination problems".

In mathematical models of the networks linking different plants and their many pollinators, such a network can continue to function very well under increasingly harsh conditions, but when conditions become extremely harsh, the entire network fails simultaneously.

A 2021 study described as the "first long-term assessment of global bee decline", which analyzed GBIF-data of over a century, found that the number of bee species declined steeply worldwide after the 1990s, shrinking by a quarter in 2006–2015 compared to before 1990.

Possible explanations

Although the existence of pollinator decline can be difficult to determine, a number of possible reasons for the theoretical concept have been proposed, such as exposure to pathogens, parasites, and pesticides; habitat destruction; climate change; market forces; intra- and interspecific competition with native and invasive species; and genetic alterations.

Honey bees are an invasive species throughout most of the world where they have been introduced, and the constant growth in the amount of these pollinators may possibly cause a decrease in native species. Light pollution has been suggested a number of times as a possible reason for the possible decline in flying insects. One study found that air pollution, such as from cars, has been inhibiting the ability of pollinators such as bees and butterflies to find the fragrances of flowers. Pollutants such as ozone, hydroxyl, and nitrate radicals bond quickly with volatile scent molecules of flowers, which consequently travel shorter distances intact. Pollinators must thus travel longer distances to find flowers.

Pollinators may also face an increased risk of extinction because of global warming due to alterations in the seasonal behaviour of species. Climate change can cause bees to emerge at times in the year when flowering plants were not available.

Consequences

Seven out of the ten most important crops in the world, in terms of volume, are pollinated by wind (maize, rice and wheat) or have vegetative propagation (banana, sugar cane, potato, beet, and cassava) and thus do not require animal pollinators for food production. Additionally crops such as sugar beet, spinach and onions are self-pollinating and do not require insects. Nonetheless, an estimated 87.5% of the world's flowering plant species are animal-pollinated, and 60% of crop plant species use animal pollinators. This includes the majority of fruits, many vegetables, and also fodder. According to the USDA 80% of insect crop pollination in the US is due to honey bees.

A study which examined how fifteen plant species said to be dependent on animals for pollination would be impacted by pollinator decline, by excluding pollinators from them with domes, found that while most species do not suffer any impacts from decline in terms of reduced fertilization rates (seed set), three species did.

The expected direct reduction in total agricultural production in the US in the absence of animal pollination is expected to be 3 to 8%, with smaller impacts on agricultural production diversity. Of all the possible consequences, the most important effect of pollinator decline for humans in Brazil, according to one 2016 study, would be the drop in income from high-value cash crops, and would impact the agricultural sector the most. A 2000 study about the economic effects of the honey bee on US food crops calculated that it helped to produce US$14.6 billion in monetary value. In 2009 another study calculated the worldwide value of the 100 crops that need pollinators at €153 billion (not including production costs). Despite the dire predictions, the theorised decline in pollinators has had no effect on food production, with yields of both animal-pollinated and non-animal-pollinated crops increasing at the same rate, over the period of supposed pollinator decline.

Possible nutritional consequences

A 2015 study looked at the nutritional consequences of pollinator decline. It investigated if four third world populations might in the future potentially be at possible risk of malnutrition, assuming humans did not change their diet or have access to supplements, but concluded that this cannot be reliably predicted. According to their model, the size of the effect that pollinator decline had on a population depends on the local diet, and vitamin A is the most likely nutrient to become deficient, as it is already deficient.

More studies also identified vitamin A as the most pollinator-dependent nutrient. Another 2015 study also modeled what would happen should 100% of pollinators die off. In that scenario, 71 million people in low-income countries would become deficient in vitamin A, and the vitamin A intake of 2.2 billion people who are already consuming less than the recommended amount would further decline. Similarly, 173 million people would become deficient in folate, and 1.23 million people would further lessen their intake. Additionally, the global fruit supply would decrease by 22.9%, the global vegetable supply would decrease by 16.3%, and the global supply of nuts and seeds would decrease by 22.1%. This would lead to 1.42 million additional deaths each year from diseases, as well as 27 million disability-adjusted life years. In a less extreme scenario wherein only 50% of pollinators die off, 700,000 additional deaths would occur each year, as well as 13.2 million disability-adjusted years.

This a picture of a melon plant. Melon plants are crops requiring a pollinator and a good source of vitamin A
A melon plant, a crop requiring a pollinator and a good source of vitamin A

One study estimated that 70% of dietary vitamin A worldwide is found in crops that are animal pollinated, as well as 55% of folate. At present, eating plants which are pollinated by animals is responsible for only 9%, 20%, and 29% of calcium, fluoride, and iron intake, respectively, with most coming from meat and dairy. 74% of all globally produced lipids are found in oils from plants that are animal pollinated, as well as 98% of vitamin C.

Solutions

Several scholars have called for application of the precautionary principle.

Efforts are being made to sustain pollinator diversity in agricultural and natural ecosystems by some environmental groups. In 2014 the Obama administration published "the Economic Challenge Posed by Declining Pollinator Populations" fact sheet, which stated that the 2015 budget proposal recommended congress appropriate approximately $50 million for pollinator habitat maintenance and to double the area in the Conservation Reserve Program dedicated to pollinator health, as well as recommending to "increase funding for surveys to determine the impacts on pollinator losses".

Some international initiatives highlight the need for public participation and awareness of pollinator conservation. Pollinators and their health have become growing concerns for the public. Around 18 states within America have responded to these concerns by creating legislation to address the issue. According to the National Conference of State Legislatures, the enacted legislation in those states addresses five specific areas relating to pollinator decline: awareness, research, pesticides, habitat protection and beekeeping.

A 2021 global assessment of the drivers of pollinator decline found that "global policy responses should focus on reducing pressure from changes in land cover and configuration, land management and pesticides, as these were considered very important drivers in most regions".

Protein aggregation

From Wikipedia, the free encyclopedia
https://en.wikipedia.org/wiki/Protein_aggregation
Misfolded proteins can form protein aggregates or amyloid fibrils, get degraded, or refold back to its native structure.

In molecular biology, protein aggregation is a phenomenon in which intrinsically-disordered or mis-folded proteins aggregate (i.e., accumulate and clump together) either intra- or extracellularly. Protein aggregates have been implicated in a wide variety of diseases known as amyloidoses, including ALS, Alzheimer's, Parkinson's and prion disease.

After synthesis, proteins typically fold into a particular three-dimensional conformation that is the most thermodynamically favorable: their native state. This folding process is driven by the hydrophobic effect: a tendency for hydrophobic (water-fearing) portions of the protein to shield themselves from the hydrophilic (water-loving) environment of the cell by burying into the interior of the protein. Thus, the exterior of a protein is typically hydrophilic, whereas the interior is typically hydrophobic.

Protein structures are stabilized by non-covalent interactions and disulfide bonds between two cysteine residues. The non-covalent interactions include ionic interactions and weak van der Waals interactions. Ionic interactions form between an anion and a cation and form salt bridges that help stabilize the protein. Van der Waals interactions include nonpolar interactions (i.e. London dispersion force) and polar interactions (i.e. hydrogen bonds, dipole-dipole bond). These play an important role in a protein's secondary structure, such as forming an alpha helix or a beta sheet, and tertiary structure. Interactions between amino acid residues in a specific protein are very important in that protein's final structure.

When there are changes in the non-covalent interactions, as may happen with a change in the amino acid sequence, the protein is susceptible to misfolding or unfolding. In these cases, if the cell does not assist the protein in re-folding, or degrade the unfolded protein, the unfolded/misfolded protein may aggregate, in which the exposed hydrophobic portions of the protein may interact with the exposed hydrophobic patches of other proteins. There are three main types of protein aggregates that may form: amorphous aggregates, oligomers, and amyloid fibrils.

Causes

Protein aggregation can occur due to a variety of causes. There are four classes that these causes can be categorized into, which are detailed below.

Mutations

Mutations that occur in the DNA sequence may or may not affect the amino acid sequence of the protein. When the sequence is affected, a different amino acid may change the interactions between the side chains that affect the folding of the protein. This can lead to exposed hydrophobic regions of the protein that aggregate with the same misfolded/unfolded protein or a different protein.

In addition to mutations in the affected proteins themselves, protein aggregation could also be caused indirectly through mutations in proteins in regulatory pathways such as the refolding pathway (molecular chaperones) or the ubiquitin-proteasome pathway (ubiquitin ligases). Chaperones help with protein refolding by providing a safe environment for the protein to fold. Ubiquitin ligases target proteins for degradation through ubiquitin modification.

Problems with protein synthesis

Protein aggregation can be caused by problems that occur during transcription or translation. During transcription, DNA is copied into mRNA, forming a strand of pre-mRNA that undergoes RNA processing to form mRNA. During translation, ribosomes and tRNA help translate the mRNA sequence into an amino acid sequence. If problems arise during either step, making an incorrect mRNA strand and/or an incorrect amino acid sequence, this can cause the protein to misfold, leading to protein aggregation.

Environmental stresses

Environmental stresses such as extreme temperatures and pH or oxidative stress can also lead to protein aggregation. One such disease is cryoglobulinemia.

Extreme temperatures can weaken and destabilize the non-covalent interactions between the amino acid residues. pHs outside of the protein's pH range can change the protonation state of the amino acids, which can increase or decrease the non-covalent interactions. This can also lead to less stable interactions and result in protein unfolding.

Oxidative stress can be caused by radicals such as reactive oxygen species (ROS). These unstable radicals can attack the amino acid residues, leading to oxidation of side chains (e.g. aromatic side chains, methionine side chains) and/or cleavage of the polypeptide bonds. This can affect the non-covalent interactions that hold the protein together correctly, which can cause protein destabilization, and may cause the protein to unfold.

Aging

Cells have mechanisms that can refold or degrade protein aggregates. However, as cells age, these control mechanisms are weakened and the cell is less able to resolve the aggregates.

The hypothesis that protein aggregation is a causative process in aging is testable now since some models of delayed aging are in hand. If the development of protein aggregates was an aging independent process, slowing down aging will show no effect on the rate of proteotoxicity over time. However, if aging is associated with decline in the activity of protective mechanisms against proteotoxicity, the slow aging models would show reduced aggregation and proteotoxicity. To address this problem several toxicity assays have been done in C. elegans. These studies indicated that reducing the activity of insulin/IGF signaling (IIS), a prominent aging regulatory pathway protects from neurodegeneration-linked toxic protein aggregation. The validity of this approach has been tested and confirmed in mammals as reducing the activity of the IGF-1 signaling pathway protected Alzheimer's model mice from the behavioral and biochemical impairments associated with the disease.

Aggregate localization

Several studies have shown that cellular responses to protein aggregation are well-regulated and organized. Protein aggregates localize to specific areas in the cell, and research has been done on these localizations in prokaryotes (E.coli) and eukaryotes (yeast, mammalian cells). From the macroscopic point of view, positron emission tomography tracers are used for certain misfolded proitein. Recently, a team of researchers led by Dr. Alessandro Crimi has proposed a machine learning method to predict future deposition in the brain. 

Bacteria

The aggregates in bacteria asymmetrically end up at one of the poles of the cell, the "older pole." After the cell divides, the daughter cells with the older pole gets the protein aggregate and grows more slowly than daughter cells without the aggregate. This provides a natural selection mechanism for reducing protein aggregates in the bacterial population.

Yeast

Most of the protein aggregates in yeast cells get refolded by molecular chaperones. However, some aggregates, such as the oxidatively damaged proteins or the proteins marked for degradation, cannot be refolded. Rather, there are two compartments that they can end up in. Protein aggregates can be localized at the Juxtanuclear quality-control compartment (JUNQ), which is near the nuclear membrane, or at the Insoluble Protein deposit (IPOD), near the vacuole in yeast cells. Protein aggregates localize at JUNQ when they are ubiquitinated and targeted for degradation. The aggregated and insoluble proteins localize at IPOD as a more permanent deposition. There is evidence that the proteins here may be removed by autophagy. These two pathways work together in that the proteins tend to come to the IPOD when the proteasome pathway is being overworked.

Mammalian cells

In mammalian cells, these protein aggregates are termed "aggresomes" and they are formed when the cell is diseased. This is because aggregates tend to form when there are heterologous proteins present in the cell, which can arise when the cell is mutated. Different mutates of the same protein may form aggresomes of different morphologies, ranging from diffuse dispersion of soluble species to large puncta, which in turn bear different pathogenicity. The E3 ubiquitin ligase is able to recognize misfolded proteins and ubiquinate them. HDAC6 can then bind to the ubiquitin and the motor protein dynein to bring the marked aggregates to the microtubule organizing center (MTOC). There, they pack together into a sphere that surrounds the MTOC. They bring over chaperones and proteasomes and activate autophagy.

Elimination

There are two main protein quality control systems in the cell that are responsible for eliminating protein aggregates. Misfolded proteins can get refolded by the bi-chaperone system or degraded by the ubiquitin proteasome system or autophagy.

Refolding

The bi-chaperone system utilizes the Hsp70 (DnaK-DnaJ-GrpE in E. coli and Ssa1-Ydj1/Sis1-Sse1/Fe1 in yeast) and Hsp100 (ClpB in E. coli and Hsp104 in yeast) chaperones for protein disaggregation and refolding.

Hsp70 interacts with the protein aggregates and recruits Hsp100. Hsp70 stabilizes an activated Hsp100. Hsp100 proteins have aromatic pore loops that are used for threading activity to disentangle single polypeptides. This threading activity can be initiated at the N-terminus, C-terminus or in the middle of the polypeptide. The polypeptide gets translocated through Hsp100 in a series of steps, utilizing an ATP at each step. The polypeptide unfolds and is then allowed to refold either by itself or with the help of heat shock proteins.

Degradation

Misfolded proteins can be eliminated through the ubiquitin-proteasome system (UPS). This consists of an E1-E2-E3 pathway that ubiquinates proteins to mark them for degradation. In eukaryotes, the proteins get degraded by the 26S proteasome. In mammalian cells, the E3 ligase, carboxy-terminal Hsp70 interacting protein (CHIP), targets Hsp70-bound proteins. In yeast, the E3 ligases Doa10 and Hrd1 have similar functions on endoplasmic reticulum proteins. On the molecular level, degradation rate of aggregates vary from protein to protein due to their different internal environments, and thus different accessibility for protease molecules.

Misfolded proteins can also be eliminated through autophagy, in which the protein aggregates are delivered to the lysosome.

Toxicity

Although it has been thought that the mature protein aggregates themselves are toxic, evidence suggests that it is in fact immature protein aggregates that are most toxic. The hydrophobic patches of these aggregates can interact with other components of the cell and damage them. The hypotheses are that the toxicity of protein aggregates is related to mechanisms of the sequestration of cellular components, the generation of reactive oxygen species and the binding to specific receptors in the membrane or through the disruption of membranes. A quantitative assay has been used to determine that higher molecular weight species are responsible for the membrane permeation. It is known that protein aggregates in vitro can destabilize artificial phospholipid bilayers, leading to permeabilization of the membrane.[]

In biomanufacturing

Protein aggregation is also a common phenomenon in the biopharmaceutical manufacturing process, which may pose risks to patients via generating adverse immune responses.

Inequality (mathematics)

From Wikipedia, the free encyclopedia https://en.wikipedia.org/wiki/Inequality...